Medicaments taken by mouth and swallowed are absorbed first into the blood perfusing the gastrointestinal (GI) tract. The venous drainage from the GI tract is first passed into the blood perfusing the liver. This means that medicaments absorbed from the lumen of the gastrointestinal tract are immediately presented to the liver, the major detoxifying organ of the body. In addition to protecting the organism from ingested toxins, the liver also metabolizes medicaments, which may be inactivated by first pass metabolism in the liver. Blood from the liver then returns to the left side of the heart via the hepatic portal vein and reaches the rest of the systemic circulation. This first pass through the liver may result in the removal of a substantial proportion of an ingested medicament.
Accordingly, other routes of drug administration have been investigated, including those involving transport across the mucous membranes. Of the various mucous membranes (e.g., oral, rectal, vaginal, ocular, nasal), drug delivery via the mucous membranes in the oral cavity seems to be the most easily tolerated by patients. In addition to avoiding the problems with traditional oral administration, drug delivery via the mucous membranes of the oral cavity has certain other advantages, due to the properties of the oral mucosa itself. For example, the mucous membranes of the oral cavity are highly vascularized and well supplied with lymphatic drainage sites.
In general, the mucous membranes of the oral cavity can be divided into five main regions: the floor of the mouth (sublingual), the cheeks (buccal), the gums (gingival), the roof of the mouth (palatal), and the lining of the lips. These regions differ from each other with respect to their anatomy, drug permeability, and physiological response to drugs. For example, in terms of relative permeability, the sublingual region is more permeable than the buccal region, which is more permeable than the palatal region. This permeability is generally related to the relative thickness and degree of keratinization of these membranes, with the sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa being thicker and non-keratinized, and the palatal mucosa being intermediate in thickness, but keratinized.
Several formulations for sublingual administration are known in the art; sublingual tablets (regular or fast-disintegrating), bio-adhesive sublingual tablets, lipid matrix sublingual tablets, thin films and sublingual sprays.
As described above, sublingual administration has certain advantages over oral administration. Being more direct, it is often faster acting, and it ensures that the substance will risk degradation only by salivary enzymes before entering the bloodstream, whereas orally administered drugs must survive passage through the hostile environment of the gastrointestinal tract, which risks degrading them, either by stomach acid or bile, or by the many enzymes therein, such as various peptidases, and other proteolytic enzymes as well as other enzymes such as monoamine oxidase (MAO). Furthermore, after absorption from the gastrointestinal tract, such drugs must pass to the liver, where they may be extensively altered; this is known as the first pass effect of drug metabolism. Due to the digestive activity of the stomach and intestines and the solubility of the GI tract, the oral route is unsuitable or very inefficient for some of the very important drugs widely used by patients. In addition, due to the more effective absorption, it is in some cases possible to reduce the dosage of the drug.
There is growing evidence that the sublingual mucosa contains an abundance of immune system cells, such as Langerhans-like dendritic cells which act as antigen presenting cells (APC) to T-cells in the cervical lymph nodes. Those cells are utilized for sublingual immune therapy mainly as anti-allergy treatment. As the suspected mechanism of Glatiramer acetate is through local immune response to the injected drug which is presented to T-cells in the subcutaneous tissue by APC the same mechanism will apply in the current invention (Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van Overtvelt L 2006. “Immune mechanisms of allergen-specific sublingual immunotherapy”. Allergy 61 (2): 151-65).
Glatiramer acetate is the generic name for the drug COPAXONE® or Copolymer 1, developed by Teva Pharmaceuticals. It is an immunomodulator, licensed in much of the world for reduced frequency of relapses in relapsing-remitting multiple sclerosis. Copaxone is administered by subcutaneous injection at a dose of 20 mg per day or 40 mg every other day. It is a non-interferon and non-steroidal medication.
Glatiramer acetate, the active ingredient of COPAXONE®, consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of Glatiramer acetate is 4,700-11,000 Daltons. Chemically, Glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt) (CAS 147245-92-9).
Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids that are found in myelin basic protein. The mechanism of action for glatiramer is unknown, although several have been proposed. Administration of glatiramer shifts the population of T cells from pro-inflammatory Th1 cells to regulatory Th2 cells that suppress the inflammatory response. Given its resemblance to myelin basic protein, glatiramer may also act as a sort of decoy, diverting an autoimmune response against myelin. The integrity of the blood-brain barrier, however, is not appreciably affected by glatiramer, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of exacerbations.
Evidence supporting the effectiveness of Glatiramer acetate in decreasing the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RR-MS) derives from two placebo-controlled trials, both of which used a Glatiramer acetate dose of 20 mg/day. A comparative trial of the approved 20 mg dose and the 40 mg dose showed no significant difference in efficacy between these doses. Various clinical trials in Glatiramer acetate are on-going. This includes studies in Clinically Isolated Syndrome patients (the PreCISe study) as well as numerous combination and induction protocols, in which Glatiramer acetate is given together with or following another active product.
PCT patent publication no. WO 2014/100639 discloses an oral tablet for transmucosal delivery, comprising Glatiramer acetate in an amount from about 10% to about 60% by weight, and one or more gel forming agents in a total amount up to about 90% by weight. Gel forming agents are defined as agents which form a matrix which allows for controlled release of an active ingredient, such as carbomers, hydroxypropylcellulose, chitosan, thiolated chitosan, thiolated carbomer, ethylcellulose, gelatine, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, gummi arabicum, xanthan gum and carrageen.
There is a long felt need in the field of multiple sclerosis (MS) therapy for novel Glatiramer acetate formulations, formulated for non-invasive administration.